The main objective of this project is to test the hypothesis that polymorphic variation at loci involved in genome maintenance relates to the onset and severity of aging phenotypes in humans and, possibly, to aging rate in general. To address this hypothesis, we propose an approach to discover genetic variants involved in genome maintenance pathways that are either enriched (beneficial alleles) or depleted (deleterious alleles) in families with exceptional longevity. For this purpose, we plan to identify functional SNP haplotypes (comprehensive candidate gene approach) of -100 genes in 5 genome maintenance pathways for association analysis with aging-related phenotypes, including exceptionally healthy aging, in individuals of an ongoing Ashkenazi Jewish Centenarian Study Cohort. The candidate genes include all genes in which heritable mutations have been found associated with accelerated aging in mice as well as genes interacting with these key genes and other genes acting in the same pathway. To ascertain the functional relevance of observed positive associations, candidate gene-SNP haplotypes will be modeled in cells and screened for various parameters of cellular fitness in short term cell culture studies to provide insight into their biological significance. Functionally relevant gene variants can then be further studied for their in vivo effect during aging by modeling them in the mouse. The results are expected to provide the first evidence that variants of the same genes found to give rise to premature aging phenotypes in the mouse are actually segregating in human populations with aging-related phenotypes and life span. This will help to translate the results obtained in the program project into targeted and personalized intervention strategies, ultimately leading to improved quality of life of the elderly population.